Muscle Innervation In Health And Disease

rudolfRüdiger Rudolf
Institute of Molecular and Cell Biology
Faculty of Biotechnology
Mannheim University of Applied Sciences
Paul-Wittsackstrasse 10
68163 Mannheim
Germany
 
Phone:  +49-621-2926804
eMail:  r.rudolf@hs-mannheim.de
Website:  http://www.imz.hs-mannheim.de/institute/research/prof-rudolf.html

 

Research Summary

In analogy to other ligand-gated ion channels of the central nervous system, nicotinic acetylcholine receptors (AChRs) located at the postsynaptic side of neuromuscular junctions (NMJs) display a complex activity-dependent intracellular trafficking, including exocytosis, endocytosis, recycling, and autophagic degradation. Activity-dependent recycling is mediated by the motor protein, myosin Va, and regulated by PKA type I. In this context, PKA function depends on proper anchoring within a NMJ-microdomain via the A-kinase anchoring protein, rapsyn. Under catabolic conditions, AChRs are degraded via autophagy employing a complex of endophilin B1, p62/SQSTM1, and the E3 ubiquitin ligase, MuRF1. The activity-dependent signals that regulate biogenesis, postsynaptic clustering, and degradation of AChR are only partially known, but require besides input from cholinergic alpha-motor neurons also direct sympathetic innervation. The latter acts on beta-adrenergic signaling and controls subsynaptic cAMP levels and nuclear localization of the transcriptional coactivator PGC1alpha. Upon local ablation of sympathetic neurons, morphology and function of NMJs dramatically deteriorate and muscle undergoes severe atrophy, but pharmacological agonists of beta-adrenergic receptors rescue these effects. Notably, beta-agonists have been recently introduced in clinics for the treatment of neuromuscular transmission disorders called congenital myasthenic syndromes, although their mechanism of action was unclear. The finding of direct sympathetic innervation of NMJs might provide a partial explanation of the clinical efficacy of beta-agonists in treating congenital myasthenic syndromes. Further research along these lines is necessary.

Structure of the Group

Group Leader:  Rüdiger Rudolf
   
   
PhD students:  Julia Dörner, Matteo Rigon, Franziska Wild, Marion Patrick Williams
   
Student:  Tatjana Straka

 

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Latest Revision: 2017-02-15
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